Aryl-substituted diazabicycloalkanes as nicotinic acetylcholine agonists

ABSTRACT

Nicotinic acetylcholine receptor agonists of formula I  
                 
wherein a, b, c, D and R are as defined in the specification, enantiomers, pharmaceutically-acceptable salts, methods of making, pharmaceutical compositions containing and methods for using the same.

TECHNICAL FIELD

This invention relates to diazabicycloalkane amides orpharmaceutically-acceptable salts thereof, processes for preparing them,pharmaceutical compositions containing them and their use in therapy.The invention also relates to compounds active as nicotinicacetylcholine receptors (nAChRs) agonists.

BACKGROUND OF THE INVENTION

The use of compounds which bind nicotinic acetylcholine receptors in thetreatment of a range of disorders involving reduced cholinergic functionsuch as Alzheimer's disease, cognitive or attention disorders, anxiety,depression, smoking cessation, neuroprotection, schizophrenia,analgesia, Tourette's syndrome, and Parkinson's disease has beendiscussed in McDonald et al. (1995) “Nicotinic Acetylcholine Receptors:Molecular Biology, Chemistry and Pharmacology”, Chapter 5 in AnnualReports in Medicinal Chemistry, vol. 30, pp. 41-50, Academic Press Inc.,San Diego, Calif.; and in Williams et al. (1994) “Neuronal NicotinicAcetylcholine Receptors,” Drug News & Perspectives, vol. 7, pp. 205-223.

DISCLOSURE OF THE INVENTION

The invention comprises compounds of formula I

wherein:

-   -   a, b and c are each 1 or 2;    -   D is oxygen or sulfur, and    -   R is selected from moieties of formulae II, III or IV:        wherein    -   R¹, and R² are independently selected from hydrogen, CN, CF₃,        halogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl or CO₂R³;    -   Ar is phenyl, or    -   Ar is a 5- or 6-membered aromatic heterocyclic moiety having 1,        2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur        where not more than one of said heteroatoms is oxygen or sulfur,        or    -   Ar is an 8-, 9- or 10-membered fused aromatic heterocyclic        moiety having 1, 2 or 3 heteroatoms selected from nitrogen,        oxygen or sulfur where not more than one of said heteroatoms is        oxygen or sulfur, or    -   Ar is an 8-, 9- or 10-membered aromatic carbocyclic ring;    -   said Ar phenyl, heterocyclic rings or carbocyclic having 0, 1 or        more substituents independently selected from hydrogen, CN, NO₂,        CF₃, halogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, aryl,        heteroaryl, OR³, CO₂R³ or NR³R⁴; where    -   R³ and R⁴ are independently at each occurrence selected from        hydrogen, C₁₋₄alkyl, aryl, heteroaryl, C(O)R⁵, C(O)NHR⁵, CO₂R⁵,        SO₂R⁶, or    -   R³, R⁴ and N in combination in the substituent —NR³R⁴ is        (CH₂)_(j)Q(CH₂)_(k) where Q is O, S, NR⁵, or a bond; j is 2, 3        or 4 and k is 0, 1 or 2; wherein    -   R⁵ at each occurrence is independently selected from hydrogen,        C₁₋₄alkyl, aryl, or heteroaryl, and    -   R⁶ at each occurrence is independently selected from C₁₋₄alkyl,        aryl, or heteroaryl.

Another embodiment of the invention comprises compounds wherein D isoxygen.

Yet another embodiment of the invention comprises compounds wherein a is1, b is 2 and c is 1.

Still another embodiment of the invention comprises compounds wherein Aris phenyl, or Ar is a 5- or 6-membered aromatic heterocyclic moietyhaving 1 or 2 heteroatoms selected from nitrogen, oxygen or sulfur wherenot more than one of said heteroatoms is oxygen or sulfur.

Another embodiment of the invention comprises compounds wherein Ar is aphenyl, furanyl or thiophenyl.

Particular compounds of the invention are those wherein a is 1, b is 2,c is 1, D is oxygen, R¹ and R² are hydrogen and Ar is phenyl, or Ar is a5- or 6-membered aromatic heterocyclic moiety having 1, 2 or 3heteroatoms selected from nitrogen, oxygen or sulfur where not more thanone of said heteroatoms is oxygen or sulfur, or Ar is an 8-, 9- or10-membered fused aromatic heterocyclic moiety having 1, 2 or 3heteroatoms selected from nitrogen, oxygen or sulfur where not more thanone of said heteroatoms is oxygen or sulfur, or Ar is an 8-, 9- or10-membered aromatic carbocyclic ring.

Particular compounds of the invention are also those wherein Ar isselected from phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, 2-furanyl or3-furanyl, 2-thienyl or 3-thienyl, benzofuran-2-yl; benzofuran-3-yl,benzo[b]thiophen-2-yl or benzo[b]thiophen-3-yl.

Particular compounds of the invention are also those wherein Ar issubstituted with one or more substituents independently selected fromCN, NO₂, CF₃, halogen, C₁ alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, aryl,heteroaryl, OR³, CO₂R³ or NR³R⁴.

Other particular compounds of the invention are:

-   (1,4-diazabicyclo[3.2.2]non-4-yl)(phenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(3-fluorophenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-fluorophenyl)methanone;-   (3-chlorophenyl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;-   (4-chlorophenyl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(3,4-dichlorophenyl)methanone;-   (3-bromophenyl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;-   (4-bromophenyl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(3-iodophenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-iodophenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-trifluoromethylphenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-methoxyphenyl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(4-trifluoromethoxyphenyl)methanone;-   (5-chlorofuran-2-yl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;-   (5-bromofuran-2-yl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;-   (5-iodoofuran-2-yl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;-   (5-chlorothiophen-2-yl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;-   (5-bromothiophen-2-yl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;-   (5-iodoothiophen-2-yl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(naphthalen-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(benzofuran-2-yl)methanone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(benzo[b]thiophen-2-yl)methanone;-   1 (1,4-diazabicyclo[3.2.2]non-4-yl)-3-phenylpropenone;-   1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-phenylpropynone;-   1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(furan-2-yl)propenone;-   1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(furan-3-yl)propenone;-   1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(thiophen-2-yl)propenone;-   1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(thiophen-3-yl)propenone;-   (1,4-diazabicyclo[3.2.2]non-4-yl)(furan-2-yl)methanone;-   (E)-1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(furan-2-yl)propenone;-   (E)-1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(thiophen-2-yl)propenone;-   (E)-1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(2-methoxyphenyl)-propenone;-   (E)-1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(2-methylphenyl)propenone;-   (1,4-diaza-bicyclo[3.2.2]non-4-yl)-(1H-indol-5-yl)-methanone;-   (1,4-diaza-bicyclo[3.2.2]non-4-yl)-(methyl-1H-indol-2-yl)-methanone,    and-   (Z)-1-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-2-fluoro-3-phenyl-propenone.

Most particular compounds of the invention are those of the examplesherein.

Each embodiment and particular form of the invention encompass alldiastereoisomers, enantiomers and pharmaceutically-acceptablederivatives and salts of compounds thereof.

Pharmaceutically-acceptable derivatives include solvates and salts. Forexample, the compounds of formula I can form acid addition salts withacids, such as the conventional pharmaceutically-acceptable acids, forexample, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric,salicylic, citric, lactic, mandelic, tartaric and methanesulfonic acids.

Compounds of the invention are useful in the treatment or prophylaxis ofhuman diseases or conditions in which activation of the α7 nicotinicreceptor is beneficial as well as in the treatment or prophylaxis ofpsychotic disorders or intellectual impairment disorders. Examples ofsuch conditions, diseases or disorders are Alzheimers disease, learningdeficit, cognition deficit, attention deficit, memory loss, AttentionDeficit Hyperactivity Disorder, Anxiety, schizophrenia, mania or manicdepression, Parkinson's disease, Huntington's disease, Tourette'ssyndrome, neurodegenerative disorders in which there is loss ofcholinergic synapse, jetlag, cessation of smoking, nicotinic addictionincluding that resulting from exposure to products containing nicotine,pain, for ulcerative colitis and irritable bowel disease.

As used herein, unless otherwise indicated, “C₁₋₄alkyl” includes but isnot limited to methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl,t-butyl, s-butyl moieties, whether alone or part of another group,C₁₋₄alkyl groups may be straight-chained or branched, and C₃₋₄alkylgroups include the cyclic alkyl moieties cyclopropyl and cyclobutyl.Alkyl groups referred to herein may have 1, 2 or 3 halogen substituents.

As used herein, unless otherwise indicated, “C₂₋₄alkenyl” includes butis not limited to 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl and3-butenyl.

As used herein, unless otherwise indicated, “C₂₋₄alkynyl” includes butis not limited to ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyland 3-butynyl.

As used herein, unless otherwise indicated, aryl refers to a phenyl ringwhich may have 1, 2 or 3 substituents selected from CN, NO₂, CF₃,halogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, OC₁₋₄alkyl, NH₂ andCO₂C₁₋₄alkyl.

As used herein, unless otherwise indicated, heteroaryl refers to a 5- or6-membered aromatic or heteroaromatic ring having 0, 1, 2 or 3 nitrogenatoms, 0 or 1 oxygen atom, and 0 or 1 sulfur atom, provided that thering contains at least one nitrogen, oxygen, or sulfur atom. Heteroarylmoieties may have one or more substituents selected from CN, NO₂, CF₃,halogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, NH₂, CO₂H, OC₁₋₄alkyl andCO₂C₁₋₄alkyl.

As used herein, unless otherwise indicated, halogen refers to fluorine,chlorine, bromine, or iodine.

Methods of Preparation

In the reaction schemes and text that follow, D and R, unless otherwiseindicated, are as defined above for formula I. The compounds of formulaI may be prepared according to the methods outlined in Scheme 1.

Compounds of formula I wherein D represents O may be prepared fromcompounds of formula III by reaction with a compound of formula II,wherein Y represents a suitable leaving group, using a suitableacylation procedure. Suitable leaving groups Y include: OH, halogen,Oalkyl, Oaryl, OCOalkyl, OCOaryl, azide. A suitable acylation procedureinvolves treatment of a compound of formula III with a compound offormula II at 0-120° C. in a suitable solvent. The presence of a base,or, when Y═OH, a coupling agent, may also be necessary for the reactionto occur. Suitable bases for the reaction include:4-(N,N-dimethylamino)pyridine, pyridine, triethylamine,N,N-diisopropylethylamine. The preferred base isN,N-diisopropylethylamine. Suitable coupling agents when Y═OH include:carbodiimides, for example 1,3-dicyclohexylcarbodiimide or1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride; phosphoniumreagents, for example benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate or benzotriazol-1-yloxytripyrrolidinophosphoniumhexafluorophosphate; and uronium reagents, for exampleO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate. Thepreferred coupling agent isO-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate.Suitable solvents for the reaction include N,N-dimethylformamide,dimethylsulfoxide, tetrahydrofuran, or chloroform. The preferred solventis N,N-dimethylformamide. The reaction is preferably performed at atemperature of 0-50° C., and most preferably at a temperature of 20-30°C.

Compounds of formula I in which D represents S may be prepared fromcompounds of formula I in which D represents O by reaction with asuitable sulfide in a suitable solvent.

The preferred sulfides are phosphorus sulfides, in particular4-methoxyphenyl-thionophosphine sulfide dimer (“Lawesson's Reagent”),and diphosphorus pentasulfide. Suitable solvents for the reactioninclude aryl hydrocarbon solvents, for example toluene or xylene. Thereaction is performed at a temperature of 0-200° C., and preferably at atemperature of 50-180° C.

It will be appreciated by one skilled in the art that certain optionalaromatic substituents in the compounds of the invention may beintroduced by employing aromatic substitution reactions, or functionalgroup transformations to modify an existing substituent, or acombination thereof. Such reactions may be effected either prior to orimmediately following the processes mentioned above, and are included aspart of the process aspect of the invention. The reagents and reactionconditions for such procedures are known in the art. Specific examplesof procedures which may be employed include, but are not limited to,electrophilic functionalisation of an aromatic ring, for example vianitration, halogenation, or acylation; transformation of a nitro groupto an amino group, for example via reduction, such as by catalytichydrogenation; acylation, alkylation or sulfonylation of an amino orhydroxyl group; replacement of an amino group by another functionalgroup via conversion to an intermediate diazonium salt followed bynucleophilic or free radical substitution of the diazonium salt; orreplacement of a halogen by another functional group for example vianucleophilic or catalysed substitution reactions.

Where necessary, hydroxy, amino, or other reactive groups may beprotected using a protecting group as described in the standard text“Protecting groups in Organic Synthesis”, 3^(rd) Edition (1999) byGreene and Wuts.

The above described reactions, unless otherwise noted, are usuallyconducted at a pressure of about one to about three atmospheres,preferably at ambient pressure (about one atmosphere). Unless otherwisestated, the above described reactions are conducted-under an inertatmosphere, preferably under a nitrogen atmosphere.

The compounds of the invention and intermediates may be isolated fromtheir reaction mixtures by standard techniques.

Acid addition salts of the compounds of formula I which may be mentionedinclude salts of mineral acids, for example the hydrochloride andhydrobromide salts; and salts formed with organic acids such as formate,acetate, maleate, benzoate, tartrate, and fumarate salts.

Acid addition salts of compounds of formula I may be formed by reactingthe free base or a salt, enantiomer or protected derivative thereof,with one or more equivalents of the appropriate acid. The reaction maybe carried out in a solvent or medium in which the salt is insoluble orin a solvent in which the salt is soluble, e.g., water, dioxane,ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents,which may be removed in vacuum or by freeze drying. The reaction may bea metathetical process or it nay be carried out on an ion exchangeresin.

The compounds of formula I exist in tautomeric or enantiomeric forms,all of which are included within the scope of the invention. The variousoptical isomers may be isolated by separation of at racemic mixture ofthe compounds using conventional techniques, e.g. fractionalcrystallization, or chiral HPLC. Alternatively the individualenantiomers may be made by reaction of the appropriate optically activestarting materials under reaction conditions which will not causeracemization,

EXAMPLE 1 (1,4-Diazabicyclo[3.2.2]non-4-yl)(phenyl)methanone

Benzoic acid (61 mg, 0.50 mmol), 1,4-diaza-bicyclo[3.2.2]nonanedihydrochloride (100 mg, 0.50 mmol), 1-hydroxybenzotriazole hydrate (68mg, 0.50 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (161 mg, 0.50 mL) and diisopropylethylamine (0.35 mL,250 mg, 2,0 mmol) in dry N,N-dimethylformamide (2 mL) wore stirred atambient temperature for 89 h. The reaction mixture was poured into 1Nsodium hydroxide solution and extracted with ethyl acetate. The ethylacetate layer was washed with 1N NaOH (1×), water (4×), brine (1×), anddried over MgSO₄. After filtration, the solvent was removed in vacuo toyield (1,4-diaza-bicyclo[3.2.2]non-4-yl)(phenyl)methanone (13 mg, 11%)as a tan waxy solid,

MS (APCI+) 231 [M+1]⁺.

EXAMPLE 2 (4-Chlorophenyl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone

4-Chlorobenzoic acid (79 mg, 0.50 mmol), 1,4-diaza-bicyclo[3.2.2]nonanedihydrochloride (100 mg, 0.50 mmol), 1-hydroxybenzotriazole hydrate (68mg, 0.50 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (161 mg, 0.50 ml) and diisopropylethylamine (0.35 mL,250 mg, 2,0 mmol) in dry N,N-dimethylformamide (2 mL) were stirred atambient temperature for 89 h. The reaction mixture was poured into 1Nsodium hydroxide solution and extracted with ethyl acetate. The ethylacetate layer was washed with 1N NaOH (1 x), water (4×), brine (1×), anddried over MgSO₄. After filtration, the solvent was removed in vacuo toyield (4-chlorophenyl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone (73 mg,55%) as a tan oil.

MS (APCI+) 265/267 [M+1]+; ¹H-NMR (300 MHz, CDCl₃): δ 7.49 (2H, d), 7.40(2H, d), 4.58-4.50 (1H, m), 3.83-3.68 (1H, m), 3.48-3.36 (1H, m),3.02-2.75 (6H, m), 2.08-1.45 (4H, m).

EXAMPLE 3 (1,4-Diazabicyclo[3.2.2]non-4-yl)(4-methoxyphenyl)methanone

4-Methoxybenzoic acid (76 mg, 0.50 mmol), 1,4-diaza-bicyclo[3.2.2]nonanedihydrochloride (100 mg, 0.50 mmol), 1-hydroxybenzotriaole hydrate (68mg, 0.50 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (161 mg, 0.50 mL) and diisopropylethylamine (0.35 mL,250 mg, 2.0 mmol) in dry N,N-dimethylformamide (2 mL) were stirred atambient temperature for 20 h. The reaction mixture was poured into 1Nsodium hydroxide solution and extracted with ethyl acetate (2×). Theethyl acetate layers were combined and washed with water (2×). Thesolvent was blown off with a stream of nitrogen to yield(1,4-diazabicyclo[3.2.2]non-4-yl)(4-methoxyphenyl)methanone (13 mg, 10%)as a colorless resin.

MS (APCI+) 261 [M+1]+; ¹H-NMR (300 MHz, CDCl₃): δ 7.33 (2H, d), 6.96(2H, d), 4.62-4.40 (1H, m), 3.80 (2H, br s), 3.78 (3H, s), 2.99-2.76(6H, m), 2.09-1.47 (4H, m).

EXAMPLE 4 (1,4-Diazabicyclo[3.2.2]non-4-yl)(benzofuran-2-yl)methanone

Benzofuran-2-carboxylic acid (81 mg, 0.50 mmol),1,4-diaza-bicyclo[3.2.2]nonane dihydrochloride (100 mg, 0.50 mmol),1-hydroxybenzotriazole hydrate (68 mg, 0.50 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(161 mg, 0.50 mL) and diisopropylethylamine (0.35 mL, 250 mg, 2.0 mmol)in dry N,N-dimethylformamide (2 mL) were stirred at ambient temperaturefor 20 h. The reaction mixture was poured into 1N sodium hydroxidesolution and extracted with ethyl acetate (2×). The ethyl acetate layerswore combined and washed with water (2×). The solvent was blown off witha stream of nitrogen to yield(1,4-diazabicyclo[3.2.2]non-4-yl)(benzofuran-2-yl)methanone (46 mg, 34%)as a yellow solid.

MS (APCI+) 271 [M+1]+; ¹H-NMR (300 MHz, CDCl₃): δ 7.74 (1H, d), 7.65(1H, d), 7.43 (1H, dd), 7.38-7.28 (2H, m), 4.59-4.38 (1H, m), 3.91-3.73(2H, m), 3.00-2.85 (6H, m), 2.09-1.91 (2H, m), 1.83-1.64 (2H, m).

EXAMPLE 5(E)-1-(1,4-Diazabicyclo[3.2.2]non-4-yl)-3-(furan-2-yl)propenone

(E)-3-Furan-2-yl-acrylic acid (69 mg, 0.50 mmol),1,4-diaza-bicyclo[3.2.2]nonane dihydrochloride (100 mg, 0.50 mmol),1-hydroxybenzotriazole hydrate (681 mg, 0.50 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(161 mg, 0.50 mL) and diisopropylethylamine (0.35 mL, 250 mg, 2.0 mmol)in dry N,N-dimethylformamide (2 mL) were stirred at ambient temperaturefor 20 h. The reaction mixture was poured into 1N sodium hydroxidesolution and extracted with ethyl acetate (2×). The ethyl acetate layerswere combined and washed with water (2×). The solvent was blown off witha stream of nitrogen to yield(E)-1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(furan-2-yl)propenone (49 mg,40%) as a beige solid.

MS (APCI+) 247 [M+1+ ¹H-NMR (300 MHz, CDCl₃): δ 7.98-7.73 (1H, m),7.42-7.23 (1H, m), 6.97-6.76 (2H, m), 6.63-6.53 (1H, m), 4.56-4.26 (1H,m), 3.80-3.66 (2H, m), 3.02-2.77 (6H, m), 1.97-1.53 (4H, m),

EXAMPLE 6(E)-1-(1,4-Diazabicyclo[3.2.2]non-4-yl)-3-(thiophen-2-yl)propenone

(E)-3-Thiophen-2-yl-acrylic acid (77 mg, 0.50 mmol),1,4-diaza-bicyclo[3.2.2]nonane dihydrochloride (100 mg, 0.50 mmol),1-hydroxybenzotriaole hydrate (68 mg, 0.50 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(161 mg, 0.50 mL) and O-diisopropylethylamine (0.35 mL, 250 mg, 2.0mmol) in dry N,N-dimethylformamide (2 mL) were stirred at ambienttemperature for 20 h. The reaction mixture was poured into 1N sodiumhydroxide solution and extracted with ethyl acetate (2×). The ethylacetate layers were combined and washed with water (2×). The solvent wasblown off with a stream of nitrogen to yield(E)-1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(thiophen-2-yl)propenone (62mg, 47%) as a colorless oil.

MS (APCI+) 263 [M+1]+; ¹H-NMR (300 MHz, CDCl₃): δ 7.73-7.55 (2H, m),7.48-7.42 (1H, m), 7.15-7.01 (1H, m), 6.96-6.76 (1H, m), 4.56-4.31 (1H,m), 3.79-3.70 (2H, m), 2.99-2.77 (6H, m), 1.97-1.54 (4H, m),

EXAMPLE 7(E)-1-(1,4-Diazabicyclo[3.2.2]non-4-yl)-3-(2-methoxyphenyl)-propenone

(E)-3-(2-Methoxyphenyl)acrylic acid (89 mg, 0.50 mmol),1,4-diazabicyclo[3.2.2]nonane dihydrochloride (100 mg, 0.50 mmol),1-hydroxybenzotriazole hydrate (68 mg, 0.50 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(161 mg, 0.50 mmol) and diisopropylethylamine (0.35 mL, 250 mg, 2.0mmol) in dry N,N-dimethylformamide (2 mL) were stirred at ambienttemperature for 20 h. The reaction mixture was poured into 1N sodiumhydroxide solution and extracted with ethyl acetate (2×). The ethylacetate layers were combined and washed with water (2×). The solvent wasblown off with a stream of nitrogen to yield(E)-1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(2-methoxyphenyl)propenone (74mg, 52%) as a yellow solid.

MS (APCI+) 287 [M+1]+: ¹H-NMR (300 MHz, CDCl₃): 7.97-7.67 (2H, m),7.41-7.30 (1H, m), 7.23-6.92 (3H, m), 4.57-4.35 (1H, m), 3.85 (3H, s),3.81-3.72 (2H, m), 3.02-2.78 (6H, m), 1.97-1.54 (4H, m).

EXAMPLE 8(E)-1-(1,4-Diazabicyclo[3.2.2]non-4-yl)-3-(2-methylphenyl)propenone

(E)-3-(2-Methylphenyl)acrylic acid (81 mg, 0.50 mmol),1,4-diazabicyclo[3.2.2]nonane dihydrochloride (100 mg, 0.50 mmol),1-hydroxybenzotriazole hydrate (68 mg, 0.50 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(161 mg, 0.50 mL) and diisopropylethylamine (0.35 mL, 250 mg, 2.0 mmol)in dry N,N-dimethylformamide (2 mL) were stirred at ambient temperaturefor 20 h. The reaction mixture was poured into 1N sodium hydroxidesolution and extracted with ethyl acetate (2×). The ethyl acetate layerswere combined and washed with water (2×). The solvent was blown off witha stream of nitrogen to yield(E)-1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(2 methylphenyl)propenone (76mg, 56%) as a colorless oil.

MS (APCI+) 271 [M+1]+; ¹H-NMR (300 MHz, CDCl₃): δ 7.83-7.64 (2H, m),7.32-7.17 (3H, m), 7.16-6.96 (1H, m), 4.57-4.41 (1H, m), 3.83-3.72 (2H,m), 3.00-2.77 (6H, m), 2.37 (3H, s), 2.00-1.54 (4H, m).

EXAMPLE 9 (1,4-Diaza-bicyclo[3.2.2]non-4-yl)-(1H-indol-5-yl)-methanone

Indole-5-carboxylic acid (40 mg, 0.25 mmol),1,4-diaza-bicyclo[3.2.2]nonane dihydrochloride (50 mg, 0,25 mmol),1-hydroxybenzotriazole hydrate (34 mg, 0.25 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (81mg, 0.25 mmol) and diisopropylethylamine (0.17 mL, 129 mg, 1.0 mmol) indry N₁N-dimethylformamide (1.5 mL) were stirred at ambient temperaturefor 24 h. The reaction mixture was poured into 1N sodium hydroxidesolution and extracted with ethyl acetate. The ethyl acetate layer waswashed with 1N NaOH (1×), water (4×), brine (1×), and dried over Na₂SO₄.After filtration, the solvent was removed in vacuo to yield 10 mg ofproduct. The reaction mixture was chromatographed with 100% EtOAc to90:10 EtOAc:7N NH₃/MeOH to give(1,4-diazabicyclo[3.2.3]non-4-yl)-(1H-indol-5-yl)-methanone (5 mg, 7%)as a pale yellow oil.

MS (APCI+) 270 [M+1]+; ¹H-NMR (300 MHz, CDCl₃): δ 8.67 (1H, s), 7.68(1H, s), 7.35 (1H, d), 7.26-7.20 (2H, m), 6.56 (1H, s), 4.81 (1H, s),3.67-3.66 (2H, m), 3.07-2.97 (6H, m), 2.13-2.00 (2H, m), 1.77 (3H, s).

EXAMPLE 10(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-(naphthylene-2-yl)-methanone

2-Napthoic acid (43 mg, 0.25 mmol), 1,4-diaza-bicyclo[3.2.2]nonanedihydrochloride (50 mg, 0.25 mmol), 1-hydroxybenzotriazole hydrate (34mg, 0.25 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (81 mg, 0.25 mmol) and diisopropylethylamine (0.17 mL,129 mg, 1,0 mmol) in dry N,N-dimethylformamide (1.5 mL) were stirred atambient temperature for 24 h. The reaction mixture was poured into 1Nsodium hydroxide solution and extracted with ethyl acetate. The ethylacetate layer was washed with 1N NaOH (1×), water (4×), brine (1×), anddried over Na₂SO₄. After filtration, the solvent was removed in vacuo toyield 50 mg of product. The reaction mixture was chromatographed with100% EtOAc to 90:10 EtOAc:7N NH₃/MeOH to give(1,4-diazabicyclo[3.2.2]non-4-yl)-naphthalen-2-yl-methanone (46 mg, 66%)as a colorless oil.

MS (APCI+) 281 [M+1]+, ¹H-NMR (300 MHz, CDCl₃): δ 7.89-7.84 (4H, m),7.61-7.46 (3H, m), 4.84 (1H, s), 3.59 (1H, s), 3.15-2.94 (7H, m), 2.18(2H, s), 1.83 (2H, s) 1.66 (1H, s).

EXAMPLE 11(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-(methyl-1H-indol-2-yl)-methanone

1-Methylindole-2-carboxylic acid (44 mg, 0.25 mmol),1,4-diazabicyclo[3.2.2]nonane dihydrochloride (50 mg, 0.25 mmol),1-hydroxybenzotriazole hydrate (34 mg, 0,25 mmol),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (81mg, 0.25 mmol) and diisopropylethylamine (0.17 mL, 129 mg, 1,0 mmol) indry N,N-dimethylformamide (1.5 mL) were stirred at ambient temperaturefor 24 h. The reaction mixture was poured into 1N sodium hydroxidesolution and extracted with ethyl acetate. The ethyl acetate layer waswashed with 1N NaOH (1×), water (4×), brine (1×), and dried over Na₂SO₄.After filtration, the solvent was removed in vacuo to yield 54 mg ofproduct. The reaction mixture was chromatographed with 100% EtOAc to90:10 EtOAc:7N NH₃/MeOH to give(1,4-diaza-bicyclo[3.2.2]non-4-yl)-(1-methyl-1H-indol-2-yl)-methanone(48 mg, 68%) as a colorless oil.

MS (APCI+) 284 (M+1]+; ¹H-NMR (300 MHz, CDCl₃): δ 7.62 (1H, d),7.39-7.26 (2H, m), 7.16 (1H, dd) 6.56 (1H, s), 4.80 (1H, s), 3.86-3.77(5H, m), 3.07-3.02 (7H, m), 2.04 (2H, s), 1.81 (2H, s) 1.66 (1H, s).

EXAMPLE 12(Z)-1-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-2-fluoro-3-phenyl-propenone

α-fluorocinnamic acid (42 mg, 0.25 mmol), 1,4-diaza-bicyclo[3.2.2]nonanedihydrochloride (50 mg, 0.25 mmol), 1-hydroxybenzotriazole hydrate (34mg, 0.25 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (81 mg, 0.25 mmol) and diisopropylethylamine (0.17 mL,129 mg, 1.0 mmol) in dry N,N-dimethylformamide (1.5 mL) wore stirred atambient temperature for 24 h. The reaction mixture was poured into 1Nsodium hydroxide solution and extracted with ethyl acetate. The ethylacetate layer was washed with 1N NaOH (1×), water (4×), brine (1×), anddried over Na₂SO₄. After filtration, the solvent was removed in vacuo toyield 61 mg of product. The reaction mixture was chromatographed with100% EtOAc to 90:10 EtOAc:7N NH₃/MeOH to give(Z)-1-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-2-fluoro-3-phenyl-propenone (54mg, 78%) as a colorless oil.

MS (APCI+) 275 [M+1]; ¹H-NMR (300 MHz, CDCl₃): δ 7.57 (2H, d), 7.40-7.29(3H, m), 6.49 (1H, d), 4.62 (1H, s), 3.75 (2H, s), 3.15-2.95 (7H, m),2.06-2.02 (2H, m), 1.79 (2H, s).

EXAMPLE 13 1-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-3-phenyl-propynone

Phenylpropionic acid (37 mg, 0.25 mmol), 1,4-diaza-bicyclo[3.2.2]nonanedihydrochloride (50 mg, 0.25 mmol), 1-hydroxybenzotriazole hydrate (34mg, 0.25 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (81 mg, 0.25 mmol) and diisopropylethylamine (0.17 mL,129 mg, 1.0 mmol) in dry N,N-dimethylformamide (1.5 mL) were stirred atambient temperature for 24 h. The reaction mixture was poured into 1Nsodium hydroxide solution and extracted with ethyl acetate. The ethylacetate layer was washed with 1N NaOH (1×), water (4×), brine (1×), anddried over Na₂SO₄. After filtration, the solvent was removed in vacuo toyield 45 mg of product. The reaction mixture was chromatographed with100% EtOAc to 90:10 EtOAc:7N NH₃/MeOH to give1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-phenyl-propynone (38 mg, 59%) as acolorless oil,

MS (APCI+) 255 [M+1]+; ¹H-NMR (300 MHz, CDCl₃): δ 7.61-7.51 (2H, m),7.45-7.33 (3H, m), 4.68-4.62 (1H, m), 4.00 (1H, t), 3.86 (1H, t),3.17-2.94 (6H, m), 2.12-1.99 (2H, m), 1.88-1.68 (3H, m).

EXAMPLE 13(1,4-diazabicyclo[3.2.2]non-4-yl)(benzo[b]thiophen-2-yl)methanonedihydrochloride

To a stirred mixture of 1,4-diazabicyclo[3.2.2]nonane dihydrochloride(100 mg, 0.51 mmol), triethylamine (0.3 mL) and a catalytic amount ofN,N-dimethylaminopyridine in dry THF (2.5 mL) at ambient temperature wasadded a solution of benzo[b]thiophene-2-carbonyl chloride in dry THF(0.5 mL). After stirring at ambient temperature for 2 hours the mixturewas partitioned between water and ethyl acetate, the organic phasesrecovered, washed with water and brine, then dried over sodium sulfate.The product obtained by concentration of the dried organic phases wassubjected to silica gel chromatography, eluting with anammoniated-chloroform to 5% methanol/chloroform gradient to give thetitle compound as a free base. The eluted material was dried to a solid.The solid was taken up in methanol, made acidic with HCl in ether (2.0M), diluted with ether and allowed to stand. The resulting salt wascollected, washed, and dried in vacuo to give the title compound as awhite solid (55.0 mg). MS (ES+) 287 (MH+).

Pharmaceutical Compositions

A further aspect of the invention relates to a pharmaceuticalcomposition for treating or preventing a condition or disorder asexemplified below arising from dysfunction of nicotinic acetylcholinereceptor neurotransmission in a mammal, preferably a human, comprisingan amount of a compound of formula I, an enantiomer thereof or apharmaceutically acceptable salt thereof, effective in treating orpreventing such disorder or condition and an inert pharmaceuticallyacceptable carrier.

For the above-mentioned uses the dosage administered will, of course,vary with the compound employed, the mode of administration and thetreatment desired. However, in general, satisfactory results areobtained when the compounds of the invention are administered at a dailydosage of from about 0.1 mg to about 20 mg per kg of animal body weight,preferably given in divided doses 1 to 4 times a day or in sustainedrelease form. For man, the total daily dose is in the range of from 5 mgto 1,400 mg, more preferably from 10 mg to 100 mg, and unit dosage formssuitable for oral administration comprise from 2 mg to 1,400 mg of thecompound admixed with a solid or liquid pharmaceutical carrier ordiluent.

The compounds of formula I, enantiomers thereof, andpharmaceutically-acceptable salts thereof, may be used on their own orin the form of appropriate medicinal preparations for enteral orparenteral administration. According to a further aspect of theinvention, there is provided a pharmaceutical composition includingpreferably less than 80% and more preferably less than 50% by weight ofa compound of the invention in admixture with an inert pharmaceuticallyacceptable diluent or carrier.

Examples of diluents and carriers are:

-   -   for tablets and dragees: lactose, starch, talc, stearic acid;    -   capsules: tartaric acid or lactose;    -   for injectable solutions: water, alcohols, glycerin, vegetable        oils;    -   for suppositories: natural or hardened oils or waxes.

There is also provided a process for the preparation of such apharmaceutical composition, which comprises mixing the ingredients.

One aspect of the invention is the use of a compound according to theinvention, an enantiomer thereof or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for the treatment orprophylaxis of one of the below mentioned diseases or conditions; and amethod of treatment or prophylaxis of one of the above mentioneddiseases or conditions, which comprises administering a therapeuticallyeffective amount of a compound according to the invention, or anenantiomer thereof or a pharmaceutically acceptable salt thereof, to apatient.

Compounds to be used according to the invention are agonists ofnicotinic acetylcholine receptors. While not being limited by theory, itis believed that agonists of the α₇ nAChR (nicotinic acetylcholinereceptor) subtype should be useful in the treatment or prophylaxis ofpsychotic disorders and intellectual impairment disorders, and haveadvantages over compounds which are or are also agonists of the α₄ nAChRsubtype. Therefore, compounds which are selective for the α₇ nAChRsubtype are preferred. The use of compounds of the invention areindicated as pharmaceuticals, in particular in the treatment orprophylaxis of psychotic disorders and intellectual impairmentdisorders. Examples of psychotic disorders include schizophrenia, maniaand manic depression, and anxiety. Examples of intellectual impairmentdisorders include Alzheimer's disease, learning deficit, cognitiondeficit, attention deficit, memory loss, and Attention DeficitHyperactivity Disorder. The compounds of the invention may also beuseful as analgesics in the treatment of pain (including chronic pain)and in the treatment or prophylaxis of Parkinson's disease, Huntington'sdisease, Tourette's syndrome, and neurodegenerative disorders in whichthere is loss of cholinergic synapses. The compounds may further beindicated for the treatment or prophylaxis of jetlag, for use ininducing the cessation of smoking, and for the treatment or prophylaxisof nicotine addiction (including that resulting from exposure toproducts containing nicotine).

It is also believed that compounds according to the invention are usefulin the treatment and prophylaxis of ulcerative colitis.

Pharmacology

The pharmacological activity of the compounds of the invention may bemeasured in the tests set out below:

Test A—Assay for Affinity at α₇ nAChR Subtype

¹²⁵I-α-Bungarotoxin (BTX) Binding to Rat Hippocampal Membranes.

Rat hippocampi were homogenized in 20 volumes of cold homogenizationbuffer (HB: concentrations of constituents (mM):tris(hydroxymethyl)aminomethane 50; MgCl₂ 1; NaCl 120; KCl 5: pH 7.4).The homogenate was centrifuged for 5 minutes at 1000×g, the supernatantwas saved and the pellet re-extracted. The pooled supernatants werecentrifuged for 20 minutes at 12000×g, washed, and resuspended in HB.Membranes (30-80 μg) were incubated with 5 nM [¹²⁵I]α-BTX, 1 mg/mL BSA(bovine serum albumin), test drug, and either 2 mM CaCl₂ or 0.5 mM EGTA[ethylene glycol-bis(β-aminoethylether)] for 2 hours at 21° C., and thenfiltered and washed 4 times over Whatman glass fibre filters (thicknessC) using a Brandel cell harvester. Pretreating the filters for 3 hourswith 1% (BSA/0.01% PEI (polyethyleneimine) in water was critical for lowfilter blanks (0.07% of total counts per minute). Nonspecific bindingwas described by 100 μM (−)-nicotine, and specific binding was typically75%.

Test B—Assay for Affinity to the α₄ nAChR Subtype

[³H]-(−)-Nicotine Binding.

Using a procedure modified from Martino-Barrows and Kellar (Mol Pharm(1987) 31:169-174), rat brain (cortex and hippocampus) was homogenizedas in the [¹²⁵I]α-BTX binding assay, centrifuged for 20 minutes at12,000×g, washed twice, and then resuspended in HB containing 100 μMdiisopropyl fluorophosphate. After 20 minutes at 4° C., membranes(approximately 0.5 mg) were incubated with 3 nM [³H]-(−)-nicotine, testdrug, 1 μM atropine, and either 2 mM CaCl₂ or 0.5 mM EGTA for 1 hour at4° C., and then filtered over Whatman glass fibre filters (thickness C)(pretreated for 1 hour with 0.5% PEI) using a Brandel cell harvester.Nonspecific binding was described by 100 μM carbachol, and specificbinding was typically 84%.

Binding Data Analysis for Tests A and B

IC₅₀ values and pseudo Hill coefficients (nH) were calculated using thenon-linear curve fitting program ALLFIT (DeLean A, Munson P J andRodbard D (1977) Am. J. Physiol., 235:E97-E102). Saturation curves werefitted to a one site model, using the non-linear regression programENZFITTER (Leatherbarrow, R. J. (1987)), yielding KD values of 1.67 and1.70 nM for the ¹²⁵I-α-BTX and [³H]-(−)-nicotine ligands respectively.Ki values were estimated using the general Cheng-Prusoff equation:K _(i) =[IC ₅₀]/((2+([ligand]/[K _(D)])^(n))^(1/n)−1)where a value of n=1 was used whenever ^(n)H<1.5 and a value of n=2 wasused when ^(n)H>1.5. Samples were assayed in triplicate and weretypically ±5%. K_(i) values were determined using 6 or more drugconcentrations. The compounds of the invention are compounds withbinding affinities (K_(i)) of less than 10 nM in either Test A or TestB, indicating that they are expected to have useful therapeuticactivity.

The compounds of the invention have the advantage that they may be lesstoxic, be more efficacious, be longer acting, have a broader range ofactivity, be more potent, produce fewer side effects, are more easilyabsorbed or have other useful pharmacological properties.

1. A compound of formula I:

wherein: a, b and c are each 1 or 2; D is oxygen or sulfur, and R isselected from moieties of formulae II, III or IV:

wherein R¹, and R² are independently selected from hydrogen, CN, CF₃,halogen, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl or CO₂R³; Ar is phenyl, orAr is a 5- or 6-membered aromatic heterocyclic moiety having 1, 2 or 3heteroatoms selected from nitrogen, oxygen or sulfur where not more thanone of said heteroatoms is oxygen or sulfur, or Ar is an 8-, 9- or10-membered fused aromatic heterocyclic moiety having 1, 2 or 3heteroatoms selected from nitrogen, oxygen or sulfur where not more thanone of said heteroatoms is oxygen or sulfur, or Ar is an 8-, 9- or10-membered aromatic carbocyclic ring, wherein said phenyl, heterocyclicrings or carbocyclic rings have 0, 1 or more substituents independentlyselected from hydrogen, CN, NO₂, CF₃, halogen, C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, aryl, heteroaryl, OR³, CO₂R³ or NR³R⁴; where R³ and R⁴ areindependently at each occurrence selected from hydrogen, C₁₋₄alkyl,aryl, heteroaryl, C(O)R⁵, C(O)NHR⁵, CO₂R⁵, SO₂R⁶, or R³, R⁴ and N incombination in the substituent —NR³R⁴ is (CH₂)_(j)Q(CH₂)_(k) where Q isO, S, NR⁵, or a bond; j is 2, 3 or 4 and k is 0, 1 or 2; wherein R⁵ ateach occurrence is independently selected from hydrogen, C₁₋₄alkyl,aryl, or heteroaryl, and R⁶ at each occurrence is independently selectedfrom C₁₋₄alkyl, aryl, or heteroaryl; or an enantiomer orpharmaceutically-acceptable salt thereof.
 2. A compound according toclaim 1, wherein D is oxygen.
 3. A compound according to claim 1,wherein a is 1, b is 2 and c is 1, or an enantiomer orpharmaceutically-acceptable salt thereof.
 4. A compound of claim 1,wherein Ar is phenyl, or Ar is a 5- or 6-membered aromatic heterocyclicmoiety having 1 or 2 heteroatoms selected from nitrogen, oxygen orsulfur where not more than one of said heteroatoms is oxygen or sulfur;or an enantiomer or pharmaceutically-acceptable salt thereof.
 5. Acompound according to claim 4, wherein Ar is a phenyl, furanyl orthiophenyl; or an enantiomer or pharmaceutically-acceptable saltthereof.
 6. A compound according to claim 1, wherein: a is 1; b is 2; cis 1; D is oxygen; R¹ and R² are hydrogen; Ar is phenyl, or Ar is a 5-or 6-membered aromatic heterocyclic moiety having 1, 2 or 3 heteroatomsselected from nitrogen, oxygen or sulfur where not more than one of saidheteroatoms is oxygen or sulfur, or Ar is an 8-, 9- or 10-membered fusedaromatic heterocyclic moiety having 1, 2 or 3 heteroatoms selected fromnitrogen, oxygen or sulfur where not more than one of said heteroatomsis oxygen or sulfur, or Ar is an 8-, 9- or 10-membered aromaticcarbocyclic ring; or an enantiomer or pharmaceutically-acceptable saltthereof.
 7. A compound according to claim 1, wherein: Ar is selectedfrom phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, 2-furanyl or 3-furanyl,2-thienyl or 3-thienyl, benzofuran-2-yl; benzofuran-3-yl,benzo[b]thiophen-2-yl or benzo[b]thiophen-3-yl; or an enantiomer orpharmaceutically-acceptable salt thereof.
 8. A compound according toclaim 1, wherein: Ar is substituted with one or more substituentsindependently selected from CN, NO₂, CF₃, halogen, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, aryl, heteroaryl, OR³, CO₂R³ or NR³R⁴; or anenantiomer or pharmaceutically-acceptable salt thereof.
 9. A compoundaccording to claim 1 selected from:(1,4-diazabicyclo[3.2.2]non-4-yl)(phenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(3-fluorophenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-fluorophenyl)methanone;(3-chlorophenyl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;(4-chlorophenyl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(3,4-dichlorophenyl)methanone;(3-bromophenyl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;(4-bromophenyl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(3-iodophenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-iodophenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-trifluoromethylphenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-methoxyphenyl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(4-trifluoromethoxyphenyl)methanone;(5-chlorofuran-2-yl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;(5-bromofuran-2-yl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;(5-iodoofuran-2-yl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;(5-chlorothiophen-2-yl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;(5-bromothiophen-2-yl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;(5-iodoothiophen-2-yl)(1,4-diazabicyclo[3.2.2]non-4-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(naphthalen-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(benzofuran-2-yl)methanone;(1,4-diazabicyclo[3.2.2]non-4-yl)(benzo[b]thiophen-2-yl)methanone;1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-phenylpropenone;1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-phenylpropynone;1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(furan-2-yl)propenone;1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(furan-3-yl)propenone;1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(thiophen-2-yl)propenone;1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(thiophen-3-yl)propenone;(1,4-diazabicyclo[3.2.2]non-4-yl)(furan-2-yl)methanone;(E)-1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(furan-2-yl)propenone;(E)-1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(thiophen-2-yl)propenone;(E)-1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(2-methoxyphenyl)-propenone;(E)-1-(1,4-diazabicyclo[3.2.2]non-4-yl)-3-(2-methylphenyl)propenone;(1,4-diaza-bicyclo[3.2.2]non-4-yl)-(1H-indol-5-yl)-methanone;(1,4-diaza-bicyclo[3.2.2]non-4-yl)-(methyl-1H-indol-2-yl)-methanone, and(Z)-1-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-2-fluoro-3-phenyl-propenone, oran enantiomer or pharmaceutically-acceptable salt thereof. 10-12.(canceled)
 13. A method of treatment or prophylaxis of psychoticdisorders, intellectual impairment disorders, human diseases orconditions in which activation of the α7 nicotinic receptor isbeneficial, Alzheimer's disease, learning deficit, cognition deficit,attention deficit, memory loss, Lewy Body Dementia, Attention DeficitHyperactivity Disorder, anxiety, schizophrenia, mania or manicdepression, Parkinson's disease, Huntington's disease, Tourette'ssyndrome, neurodegenerative disorders in which there is loss ofcholinergic synapse, jetlag, cessation of smoking, nicotine addictionincluding that resulting from exposure to products containing nicotine,pain, or ulcerative colitis which method comprises administering atherapeutically effective amount of a compound as defined in claim 1.14. A pharmaceutical composition comprising a compound of formula I, asdefined in claim 1, together with at least onepharmaceutically-acceptable excipient or diluent.